Protein LY6E as a candidate for mediating transport of adeno-associated virus across the human blood-brain barrier
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SHORT COMMUNICATION
Protein LY6E as a candidate for mediating transport of adeno-associated virus across the human blood-brain barrier Alexander M. Ille 1,2 & Eric Kishel 3 & Raoul Bodea 2 & Anetta Ille 2 & Hannah Lamont 1 & Stacy Amico-Ruvio 4 Received: 16 February 2020 / Revised: 14 July 2020 / Accepted: 4 August 2020 # Journal of NeuroVirology, Inc. 2020
Abstract The blood-brain barrier (BBB) is a major obstacle for the treatment of central nervous system (CNS) disorders. Significant progress has been made in developing adeno-associated virus (AAV) variants with increased ability to cross the BBB in mice. However, these variants are not efficacious in non-human primates. Herein, we employed various bioinformatic techniques to identify lymphocyte antigen-6E (LY6E) as a candidate for mediating transport of AAV across the human BBB based on the previously determined mechanism of transport in mice. Our results provide insight into future discovery and optimization of AAV variants for CNS gene delivery in humans. Keywords Blood-brain barrier . Central nervous system . Adeno-associated virus . LY6E . Transcytosis . Gene delivery
Introduction The blood-brain barrier: an obstacle in the treatment of CNS disorders The blood-brain barrier (BBB) is a highly selective, semipermeable diffusion barrier that separates the central nervous system (CNS) from circulating blood. The BBB functions to maintain homeostasis of the sensitive CNS neural environment and to protect against the entry of undesired substances (Obermeier et al. 2013). The BBB is composed of a
monolayer of specialized capillary endothelial cells which interact with pericytes, smooth muscle cells, neurons, and glia. This complex of endothelium in close interaction with supporting cells is collectively termed the neurovascular unit (NVU) (Sweeney et al. 2019; Weksler et al. 2005). The selectivity of the BBB results from the presence of tight junctions, which limit paracellular permeability by tightly sealing together the capillary endothelial cells (Berndt et al. 2019). Thus, only certain blood solutes such as small, lipid-soluble molecules and some gases can freely pass the BBB into the brain via diffusion across the endothelial cell membranes.
Alexander M. Ille and Eric Kishel are co-first authors. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13365-020-00890-9) contains supplementary material, which is available to authorized users. * Stacy Amico-Ruvio [email protected]
Hannah Lamont [email protected]
Alexander M. Ille [email protected]
1
Eric Kishel [email protected]
Graduate School of Biomedical Sciences, Rutgers University, Newark, NJ 07103, USA
2
STEM Biomedical, Kitchener, ON N2M 3B9, Canada
Raoul Bodea [email protected]
3
Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203, USA
Anetta Ille [email protected]
4
D’Youville College, 320 Porter Ave, Buffalo, NY 14201, USA
J. Neurovirol.
Specific lipid-insoluble substances c
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